Polygenic Risk Scores for Alzheimer's Disease in Hispanic/Latinx Populations

西班牙裔/拉丁裔人群阿尔茨海默病的多基因风险评分

• 批准号: 10662781
• 负责人: Guillaume Pare
• 金额: $ 186.86万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-15 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10662781
• 关键词: Admixture; African; African American; Alzheimer' s Disease; Amerindian; Awareness; Biological Markers; Blood; Caribbean Hispanic; Clinical; Clinical Trials; Clinical stratification; Cognitive; Data; Disease; Ethnic Origin; European; European ancestry; Exhibits; Frequencies; Gene Frequency; Genes; Genetic; Genetic Determinism; Genetic Risk; Genome; Heritability; Hispanic; Incidence; Individual; Joints; Late Onset Alzheimer Disease; Latinx; Latinx population; Linkage Disequilibrium; Measures; Methods; Mexican; Minor; Minority Groups; Modeling; Multivariate Analysis; Native American Ancestry; Neurodegenerative Disorders; Neuropsychology; Not Hispanic or Latino; Pathogenesis; Patient risk; Performance; Peruvian; Phenotype; Plasma; Polygenic Traits; Population; Prevalence; Publications; Role; Sample Size; Sampling; Sum; Testing; Universities; Variant; cohort; disorder risk; endophenotype; exome; exome sequencing; genetic information; genetic variant; genome sequencing; genome wide association study; genome-wide analysis; improved; innovation; neglect; neuroimaging; novel strategies; patient stratification; polygenic risk score; rare variant; risk prediction; risk stratification; risk variant; trait; whole genome

ABSTRACT. Late-onset Alzheimer's disease (LOAD) is the most common neurodegenerative disease, but its causes remain largely unclear. LOAD's large missing heritability has been attributed, at least partially, to mechanisms not currently investigated by traditional “single-locus” approaches. To this end, we aim to study the role of Polygenic risk scores (PRS), which capture sparse genetic information by summing up multiple risk loci across the genome, providing an individual genetic risk profile. Numerous studies have confirmed that LOAD is enriched with a polygenic component. Most of PRS have been developed in European-descend populations and no ancestry-specific PRS for LOAD have been developed in Hispanic/Latinx (HL). Furthermore, most PRS rely on common genetic variants (minor allele frequency ≥1%), neglecting the contribution of rare variants which have been shown to be critical in LOAD pathogenesis. To this end, we will generate traditional and innovative PRS leveraging large HL cohorts available at Columbia University, employing common and rare variants. Because linkage disequilibrium between common and rare variants is low, we hypothesize that these two PRS will be independent in terms of disease prediction and patient risk stratification. For common variants PRS (cvPRS), we have strong preliminary data in Caribbean Hispanics that culminated in a recent publication from our group. In addition, we will employ a new approach developed by our group, RV- EXCALIBER, which combines rare variant burden over a large number of genes into predictive rare variant polygenic risk score (rvPRS). Employing HL is particularly indicated for rvGRS because 1) they are enriched with rare variants and 2) have higher incidence and prevalence of LOAD compared to European descend populations. We will study three HL populations that exhibit different proportions of European, African and Amerindian ancestry: 1) Caribbean Hispanics 2) Mexicans and 3) Peruvians. These cohorts are deeply phenotyped for LOAD, have GWAS data and whole-exome/genome sequencing data (WGS) and plasma AD-biomarkers available for a sub-sample. We will first (Aim 1) generate a cvPRSs using common variants associated with LOAD within each Hispanic cohort. We will also generate an alternative local ancestry-weighted PRS and test the transferability of each cvPRS across HL cohorts and finally will construct a trans-ancestry PRS. Then (Aim 2) we will generate rvPRSs for those individuals with WGS and compare the performances of the two PRSs. We will also test a model that combine cvPRS and rvPRS. Finally, we will validate these new PRSs from Aim 1 and Aim 2 employing LOAD-related endophenotypes and explore a multi-trait PRS approach (Aim 3).

摘要。晚发性阿尔茨海默病（LOAD）是最常见的神经退行性疾病，但其 原因在很大程度上仍不清楚。LOAD的大缺失遗传性至少部分归因于 目前传统的“单位点”方法尚未研究的机制。为此，我们的目标是研究 多基因风险评分（PRS）的作用，它通过总结多个 基因组中的风险位点，提供个体遗传风险概况。许多研究证实， LOAD富含多基因组分。绝大多数减阻剂是在欧洲发展起来的， 在西班牙裔/拉丁裔（HL）人群中，尚未开发LOAD的祖先特异性PRS。 此外，大多数PRS依赖于常见的遗传变异（次要等位基因频率≥1%），忽略了 罕见变异的贡献，已被证明是关键的负载发病机制。为此我们将 利用哥伦比亚大学现有的大型HL队列，采用 常见和罕见的变种。由于常见和罕见变异之间的连锁不平衡很低，我们 假设这两个PRS在疾病预测和患者风险分层方面是独立的。 对于常见的变异PRS（cvPRS），我们在加勒比海西班牙裔美国人中获得了强有力的初步数据， 这是我们小组最近的一份出版物。此外，我们将采用我们集团开发的新方法，RV- EXCALIBER，它将大量基因上的罕见变异负担组合成预测性罕见变异 多基因风险评分（rvPRS）。使用HL特别适用于rvGRS，因为1）它们富含 与欧洲后裔相比，2）LOAD的发病率和患病率更高 人口。 我们将研究三个HL人口，表现出不同比例的欧洲，非洲和美洲印第安人 血统：1）加勒比海西班牙裔2）墨西哥人和3）秘鲁人。这些队列的表型进行了深入分析， LOAD，具有GWAS数据和全外显子组/基因组测序数据（WGS）和血浆AD生物标志物 可用于子样本。我们将首先（目标1）使用与以下相关的常见变体生成cvPRS： 在每个西班牙裔队列中加载。我们还将生成一个替代的本地祖先加权PRS和测试 每个cvPRS在HL队列中的可转移性，最终将构建跨血统PRS。目标（Aim） 2)我们将为那些患有WGS的个体生成rvPRS，并比较两种PRS的表现。我们 还将测试结合了联合收割机cvPRS和rvPRS的模型。最后，我们将验证目标1中的这些新PRS， 目的2采用LOAD相关内表型并探索多性状PRS方法（目的3）。